Angiogenesis is likely to play a key role in the pathogenesis of inflammatory arthritis. Several angiogenic molecules, including vascular endothelial growth factor and angiopoietin 1, are increased during rheumatoid arthritis (RA), and inhibition of angiogenesis suppresses arthritis in animal models, such as collagen-induced arthritis (CIA). We recently identified a pro-angiogenic gene, angiopoietin-like 4 (Angptl4), as the seventh most highly over-expressed mRNA in arthritic paws of mice with CIA. Expression of human Angptl4 mRNA was also substantially increased in human arthritic synovium. Angiopoietin-like 4 (Angptl4) is structurally and functionally similar to the angiopoietins, in that it specifically inhibits apoptosis of vascular endothelial cells. Expression of Angptl4 as assessed in mice and humans is limited primarily to liver, kidney, adipose tissue and inflamed synovium. This limited tissue distribution suggests that Angptl4 may play a distinct angiogenic role in arthritic tissue. Specific targeting of angiogenic events occurring within arthritic synovium may be favorable therapeutically. Angptl4 binds endothelial cells and can induce tubule formation of endothelial cells in vitro. Since Angptl4 binds to and exerts specific effects on endothelial cells, it is highly likely that a receptor for Angptl4 on endothelial cells mediates these effects. Therefore, Angptl4 and its putative receptor represent a major, targetable axis in the treatment of inflammatory arthritis. In this proposal we will develop the key reagents needed to test the hypothesis that Angptl4 increases inflammatory processes by promoting angiogenesis in arthritic synovial tissues. We directly test this hypothesis by (1) determining the effects of Angptl4 depletion on arthritis in the CIA mouse model and by (2) identifying and characterizing the receptor(s) for Angptl4 on endothelial cells.